Submissions for variant NM_000455.5(STK11):c.723T>C (p.Ala241=)

gnomAD frequency: 0.00004  dbSNP: rs533550278

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123066	SCV000166361	benign	Peutz-Jeghers syndrome	2024-01-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163237	SCV000213764	likely benign	Hereditary cancer-predisposing syndrome	2014-08-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000123066	SCV000410742	benign	Peutz-Jeghers syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000123066	SCV000487841	likely benign	Peutz-Jeghers syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001532362	SCV000517834	likely benign	not provided	2019-06-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163237	SCV000686678	likely benign	Hereditary cancer-predisposing syndrome	2015-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418469	SCV000918287	benign	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.723T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 368 fold above the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.723T>C in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001532362	SCV001747893	likely benign	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000123066	SCV002057426	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163237	SCV002533936	benign	Hereditary cancer-predisposing syndrome	2020-12-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000418469	SCV002552021	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123066	SCV004018015	benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001532362	SCV004221290	benign	not provided	2023-01-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492541	SCV004239729	likely benign	Breast and/or ovarian cancer	2022-12-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123066	SCV004818892	likely benign	Peutz-Jeghers syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000123066	SCV001551900	likely benign	Peutz-Jeghers syndrome		no assertion criteria provided	clinical testing	The STK11 p.Ala241= variant was identified in 9 of 14,208 proband chromosomes (frequency: 0.0006) from individuals with breast cancer and was present in 48 of 47,462 control chromosomes (frequency: 0.001) from healthy individuals (Momozawa 2018). The variant was identified dbSNP (rs533550278) as “with other allele”, ClinVar (classified as likely benign by Color, Ambry Genetics, GeneDx and 2 other submitters and benign by Invitae) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 45 of 269,908 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6302 chromosomes (freq: 0.0002), East Asian in 44 of 18,736 chromosomes (freq: 0.002); it was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ala241= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.